Method of photodynamically diagnosing or treating a contoured surface

ABSTRACT

A method of photodynamically diagnosing or treating a contoured surface includes topically applying 5-aminolevulinic acid to the contoured surface and irradiating the contoured surface with substantially uniform intensity visible light from a plurality of light sources generally conforming to the contoured surface. The plurality of light sources may comprise fluorescent tubes.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This application is a Continuation of U.S. application Ser. No.10/755,318, filed Jan. 13, 2004, now U.S. Pat. No. 7,190,109 which is aDivisional of U.S. application Ser. No. 09/774,084, filed Jan. 31, 2001,U.S. Pat. No. 6,709,446 which is a Divisional of U.S. application Ser.No. 09/070,772, filed May 1, 1998, now U.S. Pat. No. 6,223,071, theentire contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to photodynamic therapy using anilluminator that provides a uniform distribution of visible light. Inparticular, the present invention is directed to an apparatus and methodfor photodynamic treatment (PDT) or diagnosis (PD) of actinic keratosisof the scalp or facial areas of a patient. The present invention is alsodirected to an apparatus and method for PDT and PD of other indications(e.g., acne) and other areas of the patient (e.g., arms, legs, etc.).

As they are used here, the term “visible light” refers to radiant energyin the visible range of the electromagnetic radiation spectrum, and theterm “light” refers to radiant energy including the ultraviolet (UV),infrared (IR) and visible ranges of the electromagnetic radiationspectrum.

2. Description of Related Art

Photodynamic therapy or photochemotherapy is currently being proposed totreat several types of ailments in or near the skin or other tissues,such as those in a body cavity. For example, PDT is being proposed totreat different types of skin cancer and pre-cancerous conditions. InPDT, a patient is administered a photoactivatable agent or precursor ofa photoactivatable agent which accumulates in the tissue being diagnosedor treated. An area of the patient which includes the tissue beingdiagnosed or treated is then exposed to visible light. The visible lightcauses chemical and/or biological changes in the photoactivatable agentwhich in turn selectively locate, destroy or alter the target tissuewhile at the same time causing only mild and reversible damage to othertissues in the treatment area.

General background information on PDT using 5-aminolevulinic acid(“ALA”) as the precursor of a photoactivatable agent can be found inU.S. Pat. No. 5,079,262, entitled “Method of Detection and Treatment ofMalignant and Non-Malignant Lesions Utilizing 5-Aminolevulinic Acid,”issued to James C. Kennedy et al. on Jan. 7, 1992, and U.S. Pat. No.5,211,938, entitled “Method of Detection of Malignant and Non-MalignantLesions by Photochemotherapy of Protoporphyrin IX Precursors,” issued toJames C. Kennedy et al. on May 18, 1993. The contents of these patentsare incorporated herein by reference. The publication of James C.Kennedy et al. in the Journal of Clinical Laser Medicine and Surgery onNov. 5, 1996, entitled “Photodynamic Therapy (PDT) and Photodiagnosis(PD) Using Endogenous Photosensitization Induced by 5-AminolevulinicAcid (ALA): Mechanisms and Clinical Results,” is also incorporatedherein by reference. The “First Phase III” 1996 Annual Report by DUSAPharmaceuticals, Inc. (Tarrytown, N.Y.) contains pictures and examplesof use of the invention, and is also incorporated herein by reference.

As they are used here, the terms ALA or 5-aminolevulinic acid refer toALA itself, precursors thereof and pharmaceutically acceptable salts ofthe same.

Most conventional, non-laser light sources are comprised of just threebasic functional blocks: an emission source to generate photons (e.g., alight bulb); coupling elements to direct, filter or otherwise conductthe emitted light so that it arrives at the intended target in a usableform; and a control system to start and stop the production of lightwhen necessary. The common office fluorescent lighting fixture is a goodexample of such a system. In these fixtures, white visible light isproduced by a controlled mercury arc discharge which excites inorganicphosphor materials inside a glass tube. Energy transfer from the arccauses visible white light emission from the tube. The emitted visiblelight is directed toward the work space by reflectors in the lamphousing; the distribution of visible light to the target is oftenfurther increased by using a diffusing system. In the typical officesetting, visible light production is controlled by a simple snap switchwhich interrupts the flow of power to the lamp.

For therapeutic reasons it is desirable to have a power output which isuniform in intensity and color. In particular, it is highly desirable tohave an illuminator with a spectral output that overlaps to a largeextent with the optical activation spectrum of the targetphotosensitizer. According to one preferred embodiment of the presentinvention, blue light having wavelengths exceeding 400 nm (nanometers)is particularly advantageous for certain diagnostic purposes andtreatments, especially when ALA is the photoactivatable agent used forPD and PDT of actinic keratosis. However, visible light in other rangesof the spectrum, particularly in the green and red ranges between 400and 700 nm, may also be used.

Conventional illuminators do not produce visible light that issufficiently uniform in intensity over a contoured surface.

SUMMARY OF THE INVENTION

It is an object of the present invention, therefore, to provide animproved illuminator for PDT and/or PD.

Another object of the invention is to provide an illuminator for PDTthat produces visible light of consistent uniformity in terms of bothspectral characteristics and intensity over a diversely contouredsurface. As it is used here, the term contoured surface refers to anon-planar surface.

Yet another object of the invention is to provide an illuminator for PDTor PD which produces visible light almost entirely in a selectedwavelength range.

A further object of the present invention is to provide an illuminatorfor irradiating the face or scalp of a patient.

Yet a further object of the present invention is to provide a coolingsystem for improving the irradiance uniformity of an illuminator.

An additional object of the present invention is to provide anilluminator comprising a finite emitter that approximates the uniformoutput of an infinite plane emitter by varying the spacing of individuallight sources within the illuminator.

Yet an additional object of the present invention is to provide amonitoring system for an illuminator comprising a single visible lightsensor monitoring the visible light output of a plurality of lightsources and outputting a signal to adjust the visible light output fromthe plurality light sources.

In accomplishing the foregoing objects, there has been providedaccording to the present invention an illuminator for PDT or PD of acontoured surface. The illuminator comprises a plurality of lightsources generally conforming to the contoured surface and irradiatingthe contoured surface with substantially uniform intensity visiblelight, and a housing supporting the plurality of light sources withrespect to the contoured surface.

In accomplishing the foregoing objects, there is also provided accordingto the present invention a method of PDT or PD of a contoured surface.The method comprises topically applying 5-aminolevulinic acid to thecontoured surface, and irradiating the contoured surface withsubstantially uniform intensity visible light from a plurality of lightsources generally conforming to the contoured surface.

In accomplishing the foregoing objects, there is also provided accordingto the present invention a cooling system for an illuminator includingan elongated light source having a generally arcuate segment connectedto a generally straight segment. The cooling system comprises a plenumenclosing the light source; an intake vent to the plenum receivingambient air, the intake vent being positioned proximate a free end ofthe generally straight segment; and an exhaust vent from the plenumdischarging heated ambient air, the exhaust vent being positionedproximate a connection between the generally arcuate and straightsegments. The generally straight segment and a connection between thegenerally arcuate and straight segments receives greater coolingrelative to the generally arcuate segment.

In accomplishing the foregoing objects, there is also provided accordingto the present invention a method of providing substantially uniformintensity light from an elongated light source having a generallyarcuate segment connected to a generally straight segment. The methodcomprises providing greater cooling to the generally straight segmentrelative to the generally arcuate segment.

In accomplishing the foregoing objects, there is also provided accordingto the present invention an illuminator for emulating an infinite planeemitter. The illuminator comprises an emitting area having a perimeter,and a plurality of light sources being generally parallel to oneanother, said plurality of light sources being adapted for irradiatingsubstantially uniform intensity light from said emitting area. Lateralspacing between adjacent ones of said plurality of light sources varieswith respect to said perimeter.

In accomplishing the foregoing objects, there is also provided accordingto the present invention a monitoring system for an illuminatorirradiating a surface. The monitoring system comprises a plurality ofadjustable light sources adapted for irradiating the surface withsubstantially uniform intensity light; a light sensor being supportedwith respect to the plurality of light sources; a partition interposedbetween the light sensor and the plurality of light sources; a firstaperture in the partition adapted for admitting light from a first oneof the plurality of light sources to the light sensor, the firstaperture being spaced from the light sensor a first distance and havinga first cross-sectional area; and a second aperture in the partitionadapted for admitting light from a second one of the plurality of lightsources to the light sensor, the second aperture being spaced from thelight sensor a second distance and having a second cross-sectional area.A ratio of the first and second cross-sectional areas is proportional toinverse squares of the first and second distances; and the light sensoris adapted for monitoring light output from the first and second ones ofthe plurality of light sources and outputting a signal to adjust lightoutput from the plurality of light sources so as to provide thesubstantially uniform intensity light irradiating the surface.

In accomplishing the foregoing objects, there is also provided accordingto the present invention light for photodynamically diagnosing ortreating a contoured surface, the light coming from a plurality ofsources generally conforming to the contoured surface and irradiatingthe contoured surface with uniform intensity.

The present invention relies on similar fundamentals to that of theoffice fluorescent lighting system described above. According to anembodiment of the present invention: visible light is produced bycontour surface conforming fluorescent tubes and their associatedcontrol electronics; visible light output from these tubes is directedtoward the diagnosis or treatment area by the contour surface conformingshape of the tubes and other elements such as a reflector; andactivation of the fluorescent tubes and visible light exposure on thecontoured surface is controlled by the electronic circuitry.

The present invention differs from conventional light sources because ofthe biological requirements imposed on a PDT light source. A much higherdegree of precision and integration is required for the components ofthe present invention. Output spectrum, irradiance, and irradianceuniformity all must be controlled to assure that the properties of thedevice are suitable to deliver light to the target lesions and drive thephotodynamic reaction. To achieve this, each functional block within thepresent invention comprises carefully selected and engineeredcomponents. The principles of operation of each are described in detailbelow.

The inverse square law of optics states that the intensity of light froma point source received by an object is inversely proportional to thesquare of the distance from the source. Because of this behavior,distance from the source is an important variable in all opticalsystems. Thus, in order to achieve uniform facial or scalp irradiation,variations in output irradiance with distance must be minimized. A flatemitting surface would not deliver a uniform light dose to all contoursof the face simultaneously because the non-planar facial and scalpsurfaces could not be placed at a constant distance from the emittingsurface. To ameliorate this problem, the present invention uses aU-shaped emitting surface that more closely follows the contours of thehuman face and scalp, and minimizes lamp to target distance variationswhich in turn minimizes irradiance variations at the target.

Since the output of tubular light sources may vary with temperature,temperature distribution also plays a key role in irradiance uniformity.Further, since the tube output may vary over its length, modulation ofthe temperature distribution may be used to control irradianceuniformity of the illuminator.

Additional objects, features and advantages of the invention will be setforth in the description which follows, and in part will be clear fromthe description, or may be learned by practice of the invention. Theobjects and advantages of the invention may be realized and obtained bymeans of the instrumentalities and combinations particularly pointed outin the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of the specification, illustrate presently preferred embodiments ofthe invention, and, together with the general description given aboveand the detailed description of the preferred embodiments given below,serve to explain the principles of the invention.

FIG. 1 is a partial cross-section, front elevation view of anilluminator according to the present invention.

FIG. 2 is a partial cross-section, side elevation view of theilluminator shown in FIG. 1.

FIG. 3 is a partial cross-section, plan view of the illuminator shown inFIG. 1.

FIGS. 4A and 4B are detailed views of the fluorescent tube light sourceshown in FIG. 1.

FIGS. 5A and 5B are detailed views of the reflector shown in FIG. 1.

FIG. 6 is a detail view of the shield shown in FIG. 1.

FIG. 7 is a schematic illustration of a wiring circuit for theilluminator shown in FIG. 1.

FIG. 8 is a schematic illustration of a ballast wiring circuit for theilluminator shown in FIG. 1.

FIG. 9A is a schematic illustration of a modified wiring circuit of anilluminator according to the present invention.

FIGS. 9B-9E are schematic illustrations showing details of the wiringcircuit shown in FIG. 9A.

FIG. 10 is an illustration of a typical fluorescence emission spectrumof the fluorescent tube light source shown in FIG. 4.

FIG. 11 is a depiction of a monitoring system according to the presentinvention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Overview

According to one preferred embodiment illustrated in FIGS. 1-8, sevenU-shaped fluorescent tubes 10(1)-10(7) are driven by three electronicballasts 20. Adjusting the ballast voltage controls the output power ofthe tubes. The tubes 10(1)-10(7) are supported by a housing 30 and arecovered by a polycarbonate shield 40 which directs cooling airflowwithin the unit and prevents glass-patient contact in the event of tubebreakage. An aluminum reflector 50 located behind the tubes increasesboth the output irradiance and the uniformity of the outputdistribution. The overall dimensions of the unit are approximately 38 cmH×45 cm W×44.5 cm D. FIG. 1 shows the position of the patient's head andnose.

Exemplary Light Sources

According to a preferred embodiment of the present invention, seven 36″U-shaped F34T8 Ultra Blue fluorescent tubes 10(1)-10(7) provide amaximum visible light-emitting area 36 cm high by 46 cm wide(approximately 2850 cm²), with a minimum therapeutically active area 30cm high by 46 cm wide (approximately 1350 cm²). As shown in FIG. 1, thetubes have a generally arcuate central region 10A and arms 10B extendingfrom respective ends of the central region.

Fluorescent tubes are a type of gas discharge lamp. They utilize anelectric discharge through a low pressure gas to create a plasma whichinteracts with a fluorescing phosphor to convert electrical energy intolight. A typical fluorescent tube consists of a sealed glass tube withelectrodes, or cathodes, at both ends. The tube is internally coatedwith a uniform luminescent inorganic crystalline phosphor. The tube isfilled with a low pressure inert gas, usually argon, to which a smallamount of liquid mercury is added prior to sealing. The low internalpressure causes some of the liquid mercury to evaporate resulting in anargon/mercury atmosphere within the tube. Application of a sufficientlyhigh voltage potential across the cathodes causes the emission ofelectrons from the cathode, which diffuse along the length of the tubeand ionize the argon/mercury vapor. Once ionized, the gas mixture withinthe tube becomes conductive which permits an electrical current to flowand continue to excite the mercury atoms. The magnitude of the tubecurrent controls the number of excited atoms and hence the light outputfrom the tube. As the excited mercury atoms return to a lower energystate, they emit ultraviolet (UV) radiation. This UV radiation isabsorbed by the phosphor on the tube wall causing the phosphor tofluoresce, efficiently converting the energy of the principle resonantline of mercury to a longer wavelength. The chemistry of the phosphormaterial determines the characteristic spectral emission of the lightoutput from the lamp. This can be utilized to tune the wavelength outputof the light source to suit the requirements of the application, as isthe case in the present invention.

The output from a fluorescent tube is not inherently uniform. The outputmeasured in the immediate vicinity of the cathode is typically muchlower than the output over the rest of the tube. This occurs becauseionized gas in the area near the cathode does not emit as much UV toexcite the phosphor. This area of reduced emission is known as theFaraday dark space. To avoid uniformity problems, one embodiment of thepresent invention utilizes a plurality of U-shaped tubes 10(1)-10(7).This arrangement allows the cathodes and their low output area to belocated outside the active emitting area (effectively behind thepatient's ears). Only the more uniform center portion of the tube outputis used for patient treatment. Another advantage of the arrangement isthat uniformity can also be adjusted by varying the lateral spacing ofthe tubes (relative horizontal spacing as shown in FIG. 2). This isimportant since it is necessary to compensate for the fact that theoutput from a flat plane emitting light source drops near the edges.Varying the lateral spacing of the tubes creates the same effect asfolding the edges of a larger illuminator in on itself, thus emulatingan infinite plane emitter with a compact unit.

The U-shape minimizes the variations in distance between the emitter andthe target, providing a uniform visible light distribution to the faceor scalp of the patient; the tube dimensions were chosen based on theaverage dimensions of the adult human head. The mounting of the tubesminimizes the impact of the non-emitting area at their ends. This allowsthe present invention to be more compact and permits easier centering ofthe patient's head within the visible light sources. Moreover, the “U”shape provides the desired irradiance and irradiance uniformity forscalp and facial irradiation, and thus ensures that the proper visiblelight dosage is applied to all target areas during PDT.

The number of tubes used and the spacing between them were chosen toachieve desired uniformity and power output specifications. Optimumoutput distribution has been found to occur when seven tubes 10(1)-10(7)are placed in the chassis in a symmetric pattern with respect toopposite edges of the unit with the following approximate lateralspacing: 7 cm between the center tube 10(4) and each of the two tubes10(3), 10(5) adjacent to the center tube 10(4); 5 cm between the tubes10(3), 10(2) and 10(5), 10(6), i.e., the next pairs of tubes out fromthe center; and 3.5 cm between tubes 10(2), 10(1) and 10(6), 10(7),i.e., the outermost pairs of tubes at the sides of the unit. Theoutermost tubes 10(1), 10(7) are approximately 2.5 cm from the edges ofthe housing. The present invention provides a highly uniform outputirradiance without the use of an additional diffusing element. However,it is also envisioned that a diffusing element could also beincorporated into the shield 40.

The fluorescent tubes according to preferred embodiments of the presentinvention utilize a commercially available phosphor—Sr₂P₂O₇:Eu— that isused in the diazo blueprinting process. When this phosphor absorbs theUV radiation emitted from the mercury it produces an emission spectrumof blue light with a bandwidth having a range of 30 nm at a peakwavelength of 417 nm (nominal). A typical fluorescence emission spectrumof the tubes according to the present invention is shown in FIG. 10.According to a preferred embodiment of the present invention, thespectral output is selected to match the absorption spectrum ofprotoporphyrin IX, the photosensitizing species thought to be formedfrom ALA in target tissue. Other visible spectral outputs may beprovided when utilizing a different phosphor within the tubes. Othervisible spectral outputs may also be provided when utilizing other lightsource technologies.

Electrical Features

Achieving satisfactory performance from a fluorescent tube requires theapplication of a voltage to the tube cathodes to initiate tubeconduction and subsequently control the tube current. Fluorescent tubes,being gas discharge devices, are particularly sensitive to theelectrical voltages and currents used to drive them. Higher tubecurrents will increase the electron yield causing the output irradianceto increase. But higher currents result in higher cathode temperatures,potentially increasing the erosion of the cathode emitting material andcontamination of the tube atmosphere by material removed from thecathodes; this ultimately results in decreased tube life. Tube currentsthat are too low can result in low tube wall temperatures that may causecondensation of the mercury vapor, adversely affecting the uniformity ofthe lamp output. Furthermore, for most tube designs it is necessary toheat the cathodes to achieve proper tube starting. Control of thevoltage and/or tube current characteristics, as well as heating of thecathodes is accomplished with external electronic circuitry which isusually engineered and packaged into a single device commonly referredto as a “ballast.” There are many such ballast designs possible; theyrange from simple electromagnetic inductors to sophisticated electroniccircuits that optimize and control many aspects of tube operation.

According to a preferred embodiment of the present invention, eachballast 20 comprises three main functional sections: an input filteringcircuit, a power oscillator circuit, and a high frequency outputtransformer.

The input filter circuit rectifies the 120 VAC line voltage into aninternal DC voltage that can be utilized by the power oscillator. Thefilter also prevents disturbances on the AC line from adverselyaffecting the operation of the ballast and prevents oscillator switchingtransients from feeding back into the AC line. Lastly, this circuitprovides power factor correction so that the peak AC line current drawnby the ballasts is lower than that for a simple rectifier. It is alsopossible to operate preferred embodiments of the present invention usingDC input voltage.

The power oscillator provides the mechanism for electrical energytransfer in each ballast unit 20; it consists of a pair of switchingtransistors coupled to a resonant circuit which includes the outputtransformer. A small signal from the output transformer is fed back tothe input of the switching transistors causing them to oscillate whenthe DC voltage is applied. Energy from this oscillation is coupledthrough the transformer to the tubes. For this ballast design, themagnitude of the oscillation is proportional to the DC voltage which inturn is proportional to the AC line voltage. Because the transformer isalso connected to the tube cathodes, the magnitude of the tube currentis proportional to the AC line voltage. This is known as a non-constantwattage design and it was chosen to allow adjustment of the outputirradiance of the present invention.

The high frequency transformer couples energy to the tube, as well asperforming several other important functions. It provides electricaltransformation of voltage levels and a current limiting impedance inorder to supply the correct voltage and current to the tubes to ensureproper and safe operation. It also provides feedback to the oscillatorto help stabilize its operation and to supply a mechanism to generate aninitial high voltage starting pulse.

Additional windings of the transformer also provide a current to heatthe tube cathodes. This lowers the starting voltage requirements andreduces damage to the cathodes from the initial starting current surge.

Because of manufacturing variations in the production of the tubes, theoutput irradiance must be adjusted to meet the requirements for thespecific PDT indication. Furthermore, the output must be adjusted as thetubes age to compensate for degradation within the tubes themselves. Ina preferred embodiment of the present invention, ballasts 20 arenon-constant wattage ballasts, thus allowing the tube output to beadjusted by changing the input voltage to the ballasts. According to apreferred embodiment of the present invention, a 40% variation ispossible through the use of two buck/boost auto-transformers 60 on theAC line.

The ballast voltage may be adjusted manually or automatically. Accordingto embodiments of the present invention having manual voltageadjustment, the appropriate ballast voltage is set by a technicianmanually selecting the taps on two buck/boost auto transformers 60.Since variations in input AC line voltage affect the ballast voltage,external voltage stabilization may be used to improve the stability ofthe output. Another preferred embodiment of the present invention hasautomatic voltage adjustment including an “active” system ofmicrocontroller-activated electronic switches to eliminate the need forexternal voltage stabilization and the need for technician-adjustment ofthe ballast voltage as the tube output decreases with use. Themicrocontroller accepts input signals from optical and voltage sensorsand then activates the appropriate electronic switch to maintain outputirradiance within specified parameters. The active switching system isalso able to correct for changes in power output due to line voltage andtemperature variation during treatment; thus external line voltagestabilization is not required in a preferred embodiment of the presentinvention having the active switching system. Automatic voltageadjustment according to a preferred embodiment of the present inventionis be described more fully below.

According to one preferred embodiment of the present invention, threerapid-start electronic ballasts 20 are utilized to drive sevenfluorescent tubes 10(1)-10(7). Two of the ballasts 20(1) and 20(3) drivetwo tubes 10(1), 10(7) and 10(2), 10(6), respectively, and one ballast20(2) drives three tubes 10(3)-10(5). These ballasts convert 120 VACline voltage available from a standard wall outlet into a high frequency(˜25 kHz) sinusoidal current suitable for driving the fluorescent tubes.High frequency operation is desirable to reduce the optical outputripple which is present in all fluorescent tubes and to increase theoverall output. Output ripple is a small variation in the tube outputrelated to the sinusoidal alternating tube current used to sustain theplasma arc.

Visible Light Transmission Features

In order to utilize the visible light emitted from the back of thetubes, and to increase the uniformity of the output distribution, areflector 50 is positioned approximately 10 mm from the rear surface ofthe tubes. The reflector 50 is made of polished aluminum sheet which isbent to approximately conform to the configuration of the tubes.

The emitting area of the present invention is covered with a low UVtransmission plastic shield 40. In a preferred embodiment of the presentinvention, plastic shield 40 is made from polycarbonate. Whenfluorescent tube technology is utilized, there is a small quantity of UVemission present in the output. Polycarbonate has very low transmissionin the UV region of the spectrum and it effectively filters out anyresidual UV emission from the visible light output of the unit. Theshield 40 also protects the patient from injury in the event of tubebreakage.

Cooling Features

Since cathode and tube wall temperatures strongly affect the outputdistribution, a cooling system is provided to ensure proper bulboperation. According to an embodiment of the present invention, thecooling system comprises vents in the polycarbonate shield 40, thereflector 50 and the housing 30, as well as fans 70 to displace coolingair.

Ambient air enters the present invention through intake vents 42 in thepolycarbonate shield 40. The space between the shield 40 and thereflector 50 creates a first zone (i.e., a plenum) in which the ambientair passes over the tubes 10(1)-10(7). The ambient air is heated by thetubes, and is transferred from the first zone to a second zone betweenthe reflector 50 and the housing 30 through vents in the reflector 52.The reflector vents 52 are located at ±45° to provide the propertemperature distribution at the tube walls. Heated air is exhausted byfour fans 70 through exhaust vents 32 in the housing 30.

According to a preferred embodiment of the present invention, aplurality of intake vents 42 (thirty-six are illustrated) in thepolycarbonate shield 40 are evenly spaced along each edge directly overthe cathode area of the tubes. The vents 52 in the reflector 50 arepairs of slots machined in columns from its top to its bottom; thereflector vents 52 are directly in front of the fans 70 which arelocated at ±45° from the center of the unit.

The straight section of the tube between the cathode area and curvedsection of the “U” tubes produces slightly more output than the centerportion of the curved section. This has been attributed to differencesin the phosphor coating thickness caused by the bending process. Tofurther increase irradiance uniformity, the reflector vents 52 arelocated in the reflector 50 so that cooling air flows primarily over thestraight section and the end portions of the curved section. Lesscooling air flows over the middle of the tubes between the sets ofreflector vents 52, causing the tube wall temperature to be higher inthis region. Since the output irradiance for this tube increases (to apoint) with tube wall temperature, the hotter central region of the tubeproduces higher output irradiances than the rest of the tube andcompensates for the lower emission efficiency of the central region.

Basic Control Features

The user controls according an embodiment of the present inventioninclude a main power switch 80 located on the back of the housing 30,and an on/off key switch 90 and a timer 100, located on a side of thehousing 30. The timer 100 includes an exposure time indicator 102 thatdisplays the remaining treatment time.

The main power switch 80 is part of a fused power entry moduleconsisting of a two position rocker switch and an InternationalElectrotechnical Commission (IEC) standard power cord connector. Pushingthe rocker switch to the “1” position supplies power to the system. Thefans 70 will operate but the tubes 10(1)-10(7) will not light until thekey switch 90 is turned on and the timer 100 is set and activated. Whenthe main power switch 80 is in the “0” position all electricalcomponents within the present invention are disconnected from the ACline. The fused power entry module provides over-current protection tothe present invention and current limiting in the event of a powersurge; the main power switch 80 will not apply power to the unit ifeither fuse in this module has blown.

The key switch 90 provides a means by which use of the present inventioncan be restricted to authorized personnel. According to an embodiment ofthe present invention, operation of the timer 100 and tubes 10(1)-10(7)requires inserting the key and rotating it clockwise ¼ turn to the “ON”position. This activates the timer 100 so that the prescribed exposuretime can be entered.

According to an embodiment of the present invention, the system timer100 directly controls the operation of the fluorescent tubes10(1)-10(7). It contains three adjustment/control buttons 104: onestart/stop and two time select buttons, as well as the exposure timeindicator 102. The timer 100 is used to set the required exposure timeand to initiate visible light exposure. It automatically turns off thepresent invention tubes after the set exposure time has elapsed.

The two time select buttons 104 are preferably membrane switches thatenable the user to set the exposure time. Depressing the button 104 withthe “up” arrow increases time and depressing the button 104 with the“down” arrow decreases time. When first depressed, these buttons willchange the display reading slowly. If they remain depressed, the displaywill begin to scroll more rapidly. Small adjustments to the displayedtime can be made by quickly depressing and releasing these buttons. Inthis manner, the prescribed treatment time may set by the user.

The start/stop button 104 is a membrane switch that controls the tubeoperation; it toggles between the running and stopped states of thetubes and timer. After the exposure time has been set, depressing thisbutton 104 activates the tubes and initiates the timer countdownsequence. Depressing it a second time turns off the tubes and stops thetimer, thus providing a means for interrupting treatment if required. Ifthe start/stop button 104 is not pressed a second time, the timerautomatically turns off the tubes at the completion of the timercountdown. Treatment may also be terminated, if necessary, by rotatingthe key to the OFF position or by pushing the main power switch 80 tothe “0” position.

The exposure time indicator 102 on the timer 100 is preferably a fourdigit LED display which reads in minutes and seconds. Prior to pushingthe start/stop button 104 to begin light exposure, the display 102indicates the exposure time that has been set. When the start/stopbutton 104 is depressed to initiate treatment, the exposure timeindicator 102 will count down and display the amount of exposure timeremaining. The tubes will automatically turn off when the display reads“00:00.”

Power is supplied via a three conductor hospital grade electrical cord.The power requirements according to an embodiment of the presentinvention are 120 VAC, 2.5 amps, 60 Hz AC line voltage input that isstabilized using an external commercial voltage regulator (e.g., a SOLAMCR1000 constant voltage transformer).

Automatic Control Features

According to a preferred embodiment of the present invention, the needfor technician-adjustment of the ballast voltage as the tube outputdecreases with use is eliminated by providing automatic self-adjustmentof the ballast voltage. This has been accomplished by replacing themanual tap selection jumpers with an “active” system ofmicrocontroller-activated electronic switches (FIGS. 9A-9E). Themicrocontroller accepts input signals from optical and voltage sensorsand then activates the appropriate electronic switch to maintain outputirradiance within specified parameters. The active switching system isable to correct for changes in power output due to line voltage andtemperature variation during treatment; thus external line voltagestabilization is not required according to preferred embodiments of thepresent invention having automatic adjustment of the ballast voltage.All other components of the automatic ballast voltage adjustingembodiments of the present invention, including the tubes 10(1)-10(7),ballasts 20, reflector 50, and polycarbonate shield 40, are the same asfor the manually adjusted embodiments.

According to a preferred embodiment of the present invention, anelectronic control system 110 consists of six functional blocks. Amicrocontroller 200 is the central processing unit; it contains firmwarewhich reads the system sensors, determines the system status, controlsthe ballast voltage (and tube output), and provides user information byway of a system status LED 112 (the firmware is described in detailbelow). To achieve output irradiance in the specified range, themicrocontroller 200 monitors the tube output via a visible light sensor120 which is located behind the tube reflector 50. Referring to FIG. 11,diffuse visible light is provided to the visible light sensor 120 bymachining slots 122(3)-122(5) behind each of the center three tubes10(3)-10(5) on the reflector panel 50 just left of the center. A voltagedetection circuit 210 tells the microcontroller 200 when the timer 100has initiated its countdown sequence and also when the maximum allowableballast voltage has been reached. Using input from these sensors, themicrocontroller 200 compares the current system status with the valuesstored during calibration and determines whether ballast voltageadjustment is required. Ballast voltage adjustment is accomplished withan electronic switch array interfaced with zero-crossing opto-isolators222 to the microcontroller output lines. Finally, if the system is notfunctioning properly, or cannot produce output power in the specifiedoperating range, the microprocessor 200 activates the system status LED112 to inform the user. The functional blocks of the electronic controlsystem will now be described in greater detail.

According to a preferred embodiment of the present invention, a fullyprogrammable embedded microcontroller 200 (e.g., Microchip PIC16F84) isprovided that incorporates an arithmetic logic unit, system RAM,non-volatile storage RAM, ROM and interface circuitry into a singlemonolithic integrated circuit. The microcontroller 200 also contains anelectronically independent “watch-dog” timer circuit which is programmedto reset the CPU in the event of a microcontroller hardware failure or afirmware execution error. The microcontroller 200 interfaces. with thesystem sensors, the system status LED 112 and the electronic switcharray via twelve programmable digital I/O lines. System calibrationparameters are stored in the on-chip non-volatile RAM and all systemfirmware for controlling regulator functions is contained within theon-chip ROM storage. Firmware is programmed into ROM and verified usingexternal programming hardware.

According to a preferred embodiment of the present invention, thevisible light sensor 120 (e.g., a Texas Instruments TSL230B photosensor)is used to detect the tube output, and the output of the visible lightsensor 120 is used as the regulation criterion. In the case of theTSL230B photosensor, a large area photodiode and an integratedcurrent-to-frequency converter provide an output signal to themicrocontroller as a series of digital pulses. The direct conversion ofthe optical signal to a digital format reduces circuit complexity andeliminates calibration and drift problems associated with analogcircuitry.

The visible light sensor 120 is located behind the central tube 10(4)and the reflector panel 50 just to the left of center. In order tomonitor the visible light contribution from multiple tubes, three slots122(3)-122(5) are machined into the reflector 50 behind the centralthree tubes 10(3)-10(5). The cross sectional area and position of theseslots 122(3)-122(5) are such that the visible light sensor 120 receivesequally weighted inputs from the three bulbs 10(3)-10(5). According to apreferred embodiment of the present invention, the ratio of thecross-sectional areas for any two selected slots is proportional to theinverse squares of the selected slots' distances from the visible lightsensor 120. The visible light sensor 120 is covered with a filter tomatch its spectral responsivity to that of the optometer which was usedas the metering standard for calibration. Additionally, the visiblelight sensor 120 is covered with a glass-diffuser to further minimizethe positional dependence of the detector relative to the reflectorslots 122(3)-122(5).

The voltage detection circuit 210 performs a dual function: itcoordinates microcontroller operation with the system timer 100 andinforms the microcontroller 200 when the maximum permissible ballastvoltage has been reached. In a preferred embodiment of the presentinvention (referring to FIG. 9B), the voltage detection circuit 210comprises a CD4046 CMOS phase lock loop (PLL) 214 used as a voltagecontrolled oscillator (VCO). A sample of the line voltage present on theballast is rectified and used both to provide power to the CD4046 and todrive the VCO input. This arrangement enables the circuit to produce adigital pulse train whose frequency is proportional to ballast voltage.The pulse train is coupled via an opto-isolator 212 to themicrocontroller 200 which determines the ballast voltage by measuringthe pulse period.

Detection of system timer state is accomplished by placing the timerrelay contacts in series with the ballast supply leads. When the timer100 is off (e.g., no treatment), no voltage is present to drive eitherthe voltage detection circuit 210 or the ballasts 20. Upon detectingthis condition, the microcontroller 200 resets the system variables andloops until a pulse train (voltage) is present. Upon initiation of thetimer countdown sequence, the timer relay contacts close, supplyingvoltage to the voltage detection circuit 210 and ballasts 20. When thepresence of a pulse train is detected by the microcontroller 200, itcommences regulation (see below). Although the regulator circuit canadjust the ballast voltage, treatment duration is hardware-controlled bythe timer 100 through the series wiring of the relay contacts.

Once the visible light treatment has been initiated, the microcontroller200 monitors the VCO pulse train and compares it with a value stored inmemory during unit setup and calibration. If the measured value exceedsthe stored value, further increases in ballast voltage are inhibited.The value stored in the microcontroller memory corresponds to theballast voltage at one transformer tap setting less than its maximumrated operating voltage, preventing selection of a transformer tapsetting that would exceed the maximum ballast voltage. This techniqueminimizes unnecessary switching and ensures that the ballast voltagedoes not exceed its maximum rated operating voltage (133 VAC in apreferred embodiment of the present invention) at any time.

Referring to FIGS. 9D and 9E, the electronic switch array fortransformer tap selection comprises six thyristor electronic switches220 which connect the ballast input lines and the voltage selection tapson the buck/boost auto-transformers 60. The thyristor switches 220control gates electro-optically coupled to the microcontroller 200. Themicrocontroller 200 thus increases or decreases the voltage applied tothe ballasts 20 (increasing or decreasing the tube output) by energizingthe appropriate control gates to select the appropriate taps.

According to preferred embodiments of the present invention, the systemstatus indicator 112 shows when the output irradiance is not withinspecifications or when a control system failure has occurred. Inspectionwith a separate power meter is not necessary.

In one preferred embodiment of the present invention, the system statusindicator 112 comprises a single LED which indicates the functionalstatus of the system using a coded flash rate.

Immediately after the key is first turned to the “ON” position, the LEDflashes three times to indicate that the system function is normal andis ready for use. If this fails to occur, either the LED ormicrocontroller is not functioning correctly, or the key switch 90 hasbeen turned on, off, and on again too quickly for the microcontroller200 to reset the LED control. If the LED does not flash three timesafter shutting off the power for several seconds and restarting it, theunit should not be used.

Rapid flashing immediately after the key switch 90 is turned onindicates there is a checksum error in the microcontroller 200. Thisoccurs when a problem exists with the values stored in themicrocontroller memory for the optical regulation and ballast voltagelimits. In this instance, the unit is not operational and will notlight.

If slow flashing occurs after timed treatment has been initiated, andthe regulator attempts and fails 10 times to reduce the tube output towithin the specified range, this indicates that the output may be toohigh and the ballast voltage cannot be further reduced. This may resultfrom a microcontroller or component failure. If the LED slowly flashesduring treatment, the treatment should be discontinued because theoutput power may be higher than the specified maximum.

If a steady glow occurs after timed treatment has been initiated, andthe regulator attempts and fails 10 times to increase the tube output towithin the specified range, this indicates that the output power may betoo low and the ballast voltage cannot be further increased. If the LEDglows steadily during treatment, but does not flash, the treatment maybe continued, although the efficacy may be reduced as a result of lowtube output. The LED will turn off if the output irradiance subsequentlyincreases to above the minimum specified limit.

The microcontroller firmware has three main executable firmware modules:power-on setup, calibration and regulation. Only the power-on setup andthe regulation modules execute during patient treatments.

The power-on setup module runs only at microcontroller power up when thekey switch 90 is inserted and turned to “ON.” At this time, the systemvariables are reset and calibration values stored in non-volatile RAMare retrieved. Additionally, a checksum calculation is performed andcompared against a stored checksum. Any mismatch causes the firmware toshut down the system and initiate the LED rapid flashing code. Oncesuccessful startup has been achieved, control is transferred to theregulation module.

Upon entering the regulation module, the microcontroller 200 enters avoltage detection loop until it detects either a pulse train from thevoltage circuit or contact closure on one of the technician-accessibleservice buttons/jumpers. The internal clock and the error flags arereset in this loop. If contact service closure is detected, control istransferred to the calibration module (see below). After the exposuretime has been set on the timer 100 and the “START” button 104 has beenpressed, the microcontroller 200 detects the pulse train produced by theVCO, and enters the main regulation loop. This starts the internal clock(independent of the timer). The main regulation loop reads the output ofthe VCO, the visible light sensor 120, and the internal clock; selects anew tap switch (if required); and displays any system errors every threeseconds according to the algorithm described below. Loop executioncontinues until the timer terminates the treatment and the VCO pulsetrain.

When the timer countdown sequence is first initiated, themicrocontroller 200 sets up the switch array to apply line voltage tothe ballasts 20. During the first 2.5 minutes of the treatment (asdetermined from the internal clock), the visible light sensor 120measures the tube output, and appropriate transformer taps are selectedto keep the output irradiance between half the stored minimum andmaximum regulation limits (9.3 and 10.7 mW/cm² according to a preferredembodiment of the present invention). This is done to provide optimumtube warm-up while maintaining output irradiance within the specifiedlimits.

To allow sufficient time for the output to be within the required rangeat five minutes after any ballast voltage adjustment, themicrocontroller 200 switches the minimum regulation limit to the storedvalue (9.3 mW/cm² in a preferred embodiment of the present invention)after the first two and a half minutes of operation; the maximum limitremains unchanged. Since the regulation limits are not modified beyondthis point, the output irradiance will remain within these limits untiltreatment is terminated.

If the output cannot be maintained between the regulation limits, thesystem error flags activate the system status LED. A system error is notreported until the regulator has made ten attempts to correct thecondition. This allows time for the tubes to respond to adjustment andto prevent “nuisance” error indications.

During each loop, the microcontroller 200 measures the ballast voltagevia the VCO and sets an inhibit flag if the voltage is at maximum. Whilethis action does not directly cause an error, one may be indicated ifthe system output is too low but cannot be raised due to the inhibitflag. If the timer 100 has terminated the treatment, the VCO pulse trainis no longer present, and the microcontroller 200 returns to the voltagedetection loop until a new treatment is initiated.

Data for the calibration module is established prior to clinicalinstallation. The maximum allowable ballast voltage for the voltagedetection circuit 210 and the visible light sensor 120 signalscorresponding to the minimum and maximum regulation limits areprogrammed into the microcontroller memory using a setup/calibrationalgorithm.

To set the maximum ballast voltage, a voltage calibration jumper on theprinted circuit board is shorted, causing the microcontroller 200 toenter the voltage calibration mode. A variac is used to adjust theballast voltage to one transformer tap setting below the maximumallowable ballast voltage (127 VAC in a preferred embodiment of thepresent invention). Shorting the voltage calibration jumper a secondtime stores both this voltage value and a checksum in themicrocontroller non-volatile memory. Each time the voltage calibrationjumper is shorted, the system status LED flashes to indicate that theaction has been completed.

Next, the maximum and minimum regulation limits are stored in themicrocontroller memory by switching to the optical calibration mode. Areference UDT optometer (e.g., a UDT S370 power meter with a 247detector/cosine diffuser assembly), is placed at a reference point.According to a preferred embodiment of the present invention, thereference point is 3″ from the polycarbonate shield 40 at the center ofthe therapeutically active area. The ballast voltage is adjusted with avariac to obtain the desired maximum irradiance on the optometer. Thecorresponding output signal from the visible light sensor 120 is inputto microcontroller memory as the maximum output limit. This procedure isrepeated, adjusting the output to obtain the desired minimum irradianceon the optometer and setting the minimum limit of the regulator.Finally, a checksum is stored and the microcontroller 200 returns to thepower-on setup module, commencing normal operation. As with the voltagecalibration, the system status LED flashes each time calibration datahas been stored.

It has been found that, according to a preferred embodiment of thepresent invention, the measured output over the active emitting area iswithin 70% of the measured maximum when measured with a cosine responsedetector at distances of 4″ and 2″, and within 60% of the measuredmaximum over all operation distances.

Exemplary Diagnosis and Treatment Methods

One example of a treatment method for precancerous lesions, such asactinic keratosis, by PDT utilizing an illuminator described above inconjunction with 5-aminolevulinic acid (ALA) will now be described.

Essentially anhydrous ALA is admixed with a liquid diluent just prior toits use. The ALA admixture is topically applied to the lesions using apoint applicator to control dispersion of the ALA admixture. A suitableapplicator is described in U.S. patent application Ser. No. 08/962,294(filed Oct. 31, 1997), and ALA is generally discussed further in U.S.patent application Ser. No. 08/921,664 (filed Sep. 2, 1997). The entirecontents of these applications are incorporated herein by reference.

After the initial application of the ALA admixture has dried, one ormore subsequent applications may be similarly applied. Approximately 2mg/cm² of ALA is administered. Formation of photosensitive porphyrin andphotosensitization of the treated lesions occurs over the next 14-18hours, during which time exposure to direct sunlight or other brightlight sources should be minimized. Between 14 and 18 hours afteradministration of the ALA, the lesions are irradiated by an illuminatoraccording to the present invention. The illuminator irradiates thelesions with a uniform blue light for a prescribed period. According toa preferred treatment, the visible light has a nominal wavelength of 417nm.

The invention thus provides a method for photodynamically diagnosing ortreating a contoured surface of a patient which includes providing theilluminator described above, placing the patient in the illuminator, andilluminating the patient to diagnose or treat the patient. As describedin the documents referred to above, the patient may be illuminated totreat actinic keratoses, acne, photo damaged skin, cancer, warts, orpsoriasis. The method can also be used to remove hair and diagnosecancer.

Since total light Dose (J/cm²)=Irradiance (W/cm²)×Time (sec), the onlyadditional parameter that needs to be controlled for delivery of thecorrect treatment light dose is exposure time. This is accomplished in apreferred embodiment of the present invention by the timer whichcontrols electrical power to the ballasts and which can be set by thephysician. Data has shown that 10 J/cm² delivered from a source with anirradiance density of 10 mW/cm² produces clinically acceptable results.From the equation above, this light dose will require an exposure timeof 1000 seconds (16 min. 40 sec). A selected light dose may also beadministered by additionally or alternatively varying the irradiancedensity.

Additional advantages and modifications will readily occur to thoseskilled in the art. Therefore, the invention in its broader aspects isnot limited to the specific details, and representative devices, shownand described herein. Accordingly, various modifications may be madewithout departing from the spirit and scope of the general inventiveconcept as defined by the appended claims and their equivalents.

1. A method of photodynamically diagnosing or treating a contouredsurface, comprising: topically applying 5-aminolevulinic acid to thecontoured surface; and irradiating the contoured surface withsubstantially uniform intensity visible light from a plurality of lightsources generally conforming to the contoured surface, wherein theplurality of light sources comprises fluorescent tubes.
 2. The methodaccording to claim 1, wherein the 5-aminolevulinic acid is in a carrier.3. The method according to claim 1, further comprising: applying5-aminolevulinic acid in successive applications.
 4. The methodaccording to claim 1, comprising the step of topically applying5-aminolevulinic acid to the contoured surface and irradiating thecontoured surface to treat actinic keratosis.
 5. The method according toclaim 4, comprising the step of admixing the 5-aminolevulinic acid witha vehicle just prior to its use.
 6. The method according to claim 1,comprising the step of topically applying 5-aminolevulinic acid to thecontoured surface and irradiating the contoured surface to treat acne.7. The method according to claim 6, comprising the step of admixing the5-aminolevulinic acid with a vehicle just prior to its use.
 8. Themethod according to claim 1, comprising the step of topically applying5-aminolevulinic acid to the contoured surface and irradiating thecontoured surface to treat photo damaged skin.
 9. The method accordingto claim 8, comprising the step of admixing the 5-aminolevulinic acidwith a vehicle just prior to its use.
 10. The method according to claim1, comprising the step of topically applying 5-aminolevulinic acid tothe contoured surface and irradiating the contoured surface to treatcancer.
 11. The method according to claim 10, comprising the step ofadmixing the 5-aminolevulinic acid with a vehicle just prior to its use.12. The method according to claim 1, comprising the step of topicallyapplying 5-aminolevulinic acid to the contoured surface and irradiatingthe contoured surface to treat warts.
 13. The method according to claim12, comprising the step of admixing the 5-aminolevulinic acid with avehicle just prior to its use.
 14. The method according to claim 1,comprising the step of topically applying 5-aminolevulinic acid to thecontoured surface and irradiating the contoured surface to treatpsoriasis.
 15. The method according to claim 14, comprising the step ofadmixing the 5-aminolevulinic acid with a vehicle just prior to its use.16. The method according to claim 1, comprising the step of topicallyapplying 5-aminolevulinic acid to the contoured surface and irradiatingthe contoured surface to remove hair.
 17. The method according to claim16, comprising the step of admixing the 5-aminolevulinic acid with avehicle just prior to its use.
 18. The method according to claim 1,comprising the step of topically applying 5-aminolevulinic acid to thecontoured surface and irradiating the contoured surface to diagnosecancer.
 19. The method according to claim 18, comprising the step ofadmixing the 5-aminolevulinic acid with a vehicle just prior to its use.20. The method according to claim 1, comprising the step of topicallyapplying 5-aminolevulinic acid to the contoured surface and irradiatingthe contoured surface to treat a pre-cancerous condition.
 21. The methodaccording to claim 20, comprising the step of admixing the5-aminolevulinic acid with a vehicle just prior to its use.
 22. Themethod according to claim 1, comprising the step of admixing the5-aminolevulinic acid with a vehicle just prior to its use.
 23. Themethod according to claim 1, wherein the contoured surface is irradiatedwith light substantially entirely within the blue region.
 24. A methodof photodynamically diagnosing or treating a contoured surface,comprising: topically applying 5-aminolevulinic acid to the contouredsurface; and irradiating the contoured surface with substantiallyuniform intensity visible light from a plurality of light sourcesgenerally conforming to the contoured surface, wherein the contouredsurface is irradiated with light substantially entirely within the blueregion.
 25. The method according to claim 1, comprising the step ofadmixing the 5-aminolevulinic acid with a vehicle just prior to its use.26. A method of photodynamically diagnosing or treating a contouredsurface, comprising: topically applying 5-aminolevulinic acid to thecontoured surface; and irradiating the contoured surface withsubstantially uniform intensity visible light from a plurality of lightsources generally conforming to the contoured surface, wherein saidirradiating comprises approximately 1000 seconds of light having anominal peak wavelength of 417±5 nanometers and a nominal bandwidth of30 nanometers.